There is an urgent need for novel therapies capable of reducing mortality and permanent neurological deficits in victims of stroke. The development of effective neuroprotective strategies requires a comprehensive understanding of the diverse mechanisms of ischemic brain damage that are responsible for neuronal death. Pathophysiological processes associated with neuronal death in stroke and other degenerative diseases are usually investigated separately. However, stroke and degenerative diseases may have common links as mechanisms/genes defined for one neurodegenerative condition might also be central in stroke. Because stroke can cause or accelerate latent or progressive neurodegenerative events, it appears reasonable to investigate common molecular links between stroke and neurodegenerative diseases as to provide a new perspective on disease pathogenesis. Using cellular and animal models of ischemic injury, we demonstrate that a-synuclein, a protein classically associated with Parkinson's disease, plays pivotal roles in stroke-induced protein aggregation and neuronal damage. Cerebral ischemia induces a-synuclein accumulation and aggregation suggesting that the pathological processes culminating in neuronal cell injury in stroke and Parkinson's disease may be linked, and that a-synuclein may be the key to this link. In the current study, we propose to dissect a-synuclein pathology in cerebral ischemia and determine the underlying mechanism whereby a-synuclein accumulates in vulnerable neurons. A better understanding of the underlying mechanism by which a-synuclein accumulates in vulnerable neurons after cerebral ischemia could lead to a feasible therapeutic strategy for preventing a-synuclein induced pathology in stroke and related neurological disorders. PUBLIC HEALTH RELEVANCE: Misfolding and aggregation of proteins are common threads linking a number of important human diseases. Though abnormal protein aggregates are characteristic features of chronic neurodegenerative disorders, they are also found in acute pathological states of the brain such as stroke or cerebral ischemia. We found that transient focal cerebral ischemia induces the continuous accumulation of insoluble a-synuclein, a protein that has been linked to the pathogenesis of Parkinson's disease. We propose to dissect a-synuclein pathology in cerebral ischemia and determine the underlying mechanism whereby a-synuclein accumulates in vulnerable neurons. Our studies will provide new perspectives on the pathological role of a-synuclein in cerebral ischemia and potential cellular targets for blocking a-synuclein accumulation.